This application is a 371 of PCT/JP01/04327, filed May 23, 2001.
The present invention relates to novel expanded porphyrins that are macrocycles comprising of alternate arrangement of more than six of pyrrole units bridged by a methine group whose hydrogen is substituted with Ar-group (hereinafter xe2x80x9ca methine carbonxe2x80x9d will be called as C-1) at xcex1 position of the pyrrole, and further relates the easy synthetic method of these expanded porphyrins.
In recent years, much attention has been paid to the exploration of chemistry of porphyrins and other tetrapyrrolic microcycles due to their high potential in a variety of fields. Similarly, expanded porphyrins that bear more than five pyrroles have attracted considerable attention in light of their promising properties. In contrast, there are only scattered reports on meso-aryl substituted expanded porphyrins that are structurally homologous to tetrakis-meso-aryl porphyrin in respect of alternate conjugative arrangement of pyrrole and methine carbon. Expected high potential of these meso-aryl expanded porphyrins stem from their characteristic interesting properties that are not found for porphyrins; namely, the larger cyclic n-network, red-shifted absorption bands, more flexible conformation of the macrocycles, and coordination ability of more than two metal ions.
Synthesis of expanded porphyrins with six pyrrole subunits were reported with trivial names of rubyrin (Sessler, J. L. et al., 1991) and hexaphyrin (Gossaurer, A., 1983). These compounds have attracted intense interests in light of the expected recognizing ability of particular tumor cells and the cell membrane permeability on the basis of the known properties of related porphyrins and thus a potential application as the stable drug delivery system. Further, expanded porphyrins, that are called as decaphyrin due to the constituent ten pyrrole subunits, were prepared and aroused a wide interest in their ability to form novel chelates with a variety of metals. Among them, a stable gadolinium Gd(III) decaphyrin has been demonstrated to be usable as a MRI diagnosis drug and several other metal complexes of decaphyrins are useful for photodynamic therapy owing to their red-shifted absorption bands. (WO96/21665, opened to the public on Jul. 18, 1996).
However, in these previous examples, the constituent pyrrole subunits are linked not with a methine C-1 subunit but sometimes linked directly. In this sense, meso-aryl expanded porphyrins that have a regular, alternate arrangement of a pyrrole and a methine C-1 subunit and thus can be regarded as real homologs of porphyrins with the name of xe2x80x9clegitimatexe2x80x9d expanded porphyrins are quite rare. There is no established procedure that allows the preparation of a series of meso-aryl expanded porphyrins.
Rothemund-Lindsey protocol has been used for effective preparation of porphyrins by treating an equimolar mixture of aryl aldehyde and pyrrole with acid catalyst in CHCl3 or CH2Cl2 to form a equilibrated mixture of a cyclic porphyrinogen and linear oligomeric pyrromethene-oligomers that is subsequently oxidized to give a porphyrin and oligomeric tars. A typical synthetic procedure was reported by J. S. Lindsey et al. in Journal of Organic Chemistry vol 52, No.5 827-836 (1987), in which meso-tetraaryl and meso-tetraalkylporphyrins were prepared from the corresponding aldehyde and pyrrole with aid of boron trifluoride-etherate or trifluoroacetic acid as an acid catalyst and p-choranil as an oxidant.
Lindsey et. al. have reported that the yield of porphyrin by said synthesis method depends largely on the substrate concentrations, and under the certain acid concentration condition the porphyrin yield was reported to reach the maximum at the substrate concentration of ca. 10 mM, and at the substrate concentration of 1 mM or 100 mM, the yield of porphyrin has been reported to be reduced to approximately a half for the both cases. The reduction of the porphyrin yields at 1 mM or 100 mM concentrations has not been rationalized and any discrete products other than a porphyrin were not expected so far.
The object of the present invention is to establish a reliable synthetic method that allows the synthesis of a series of meso-aryl expanded porphyrins with the alternate arrangement of pyrrole subunit and a C-1 methine subunit in a cyclic manner. The another object is to provide a simplified method for preparation of meso-aryl expanded porphyrins comprising, forming a macrocycle by alternate bonding of more than 6 pyrrole units with methine whose hydrogen is substituted by Ar group at xcex1 position of the pyrrole. The inventor of the present invention found a very reliable synthetic procedure that allows the preparation of a series of meso-aryl expanded porphyrins. The inventor of the present invention has found that meso-aryl expanded porphyrins can be prepared from the Rothemund-Lindsey reaction of 2,6-disubstituted aromatic aldehyde and pyrrole under rather concentrated conditions at 6 times level. 9-Formylanthracene and cyclohexane carboaldehyde are also employed in this synthesis. Therefore it is now concluded that the above-mentioned objects are now accomplished.
The first one of the present invention is the finding of expanded porphyrins that are macrocycles comprising of alternate arrangement of more than six of pyrrole units bridged by a methine group whose hydrogen is substituted with Ar-group (hereinafter xe2x80x9ca methine carbonxe2x80x9d will be called as C-1) at xcex1 position of the pyrrole (wherein Ar is 2,6-substituted phenyl group which can possess a substituent at the 3, 4, or 5 position, a 9-anthryl group which can possess a substituent, or a cyclohexyl group which can possess a substituent. The said substituents at 2 and 6 positions can be selected independently from fluoro, chloro, bromo, iodo, lower alkyl group of carbon number 1 to 4, and lower alkoxy group, the said substituents at the 3-5 positions of Ar-group and those of 9-anthryl and cyclohexyl groups can be selected from the group consisting of substituted or non-substituted alkyl of carbon number 5 or 6, alkenyl group, alkynyl group, substituted or non-substituted aryl group, alkyl or aryl sulfonyl group, alkyl or aryl cyano group, cyano group, nitro group, amino group, carboxy group, carboalkoxy group or ester, amide and salt thereof and specific group having well-known target specific substrate besides above mentioned substituents at 2 and 6 positions. Each Ar-group can be different.
Favorably, the first one of the present invention is the novel expanded porphyrins forming a macrocycle by alternate bonding of more than 6 pyrrole units with methine whose hydrogen is substituted by Ar group at xcex1 position of pyrrole obtained by reacting pyrrole with 2,6 substituted benzaldehydes which can possess substituent at other position, 9-formylanthracenes which can possess substituent or cyclohexane carbaldehydes which can possess substituent under the presence of acid catalyst and by oxidizing with an oxidizing agent. More desirably, the first one of the present invention is the novel expanded porphyrins wherein aldehyde compound is selected from the group consisting of 2,6-difluorobenzaldehyde, 2,3,6-trifluorobenzaldehyde, 2,4,6-trifluorobenzaldehyde, 2,3,4,5,6-pentafluorobenzaldehyde, 2,6-dichlorobenzaldehyde, 2,3,6-trichlorobenzaldehyde, 2,4,6-trichlorobenzaldehyde, 2,3,4,5,6-pentachlorobenzaldehyde, 2,6-dimethylbenzaldehyde, 2,4,6-trimethylbenzaldehyde, cyclohexanecarbo aldehyde or 9-formylanthracenes, more favorably is the novel expanded porphyrins represented by following compounds selected from the group A forming a macrocycle by alternate bonding of more than 6 pyrrole units with methine whose hydrogen at xcex1 position of the pyrrole is substituted by Ar group at xcex1 position of pyrrole. 
(wherein Ar is 2,6-substituted phenyl group which can possess a substituent on 3, 4 or 5 position, 9-anthranil group which can possess a substituent or cyclohexyl group which can possess a substituent. And said substituent at 2 and 6 positions can be selected independently from the group consisting of fluoro, chloro, bromo, iodide, lower alkyl of carbon number 1 to 4 or lower alkoxy, substituent at 3-5 positions, 9-anthryl group and cyclohexyl group can be selected independently from the group consisting of substituted or non-substituted alkyl of carbon number 5 or 6, alkenyl group, alkynyl group, substituted or non-substituted aryl group, alkyl or aryl sulfonyl group, alkyl or aryl cyano group, cyano group, nitro group, amino group, carboxy group, carboalkoxy group or ester, amide and salt thereof and specific group having well-known target specific besides above mentioned substituents at 2 and 6 positions. Each Ar can be different).
These compounds are useful as an intermediate to obtain an useful compound for various uses through forming coordination compound with more than two metals or through exhibiting biological effects that are well-known for porphyrins or expanded porphyrins.
The second one of the present invention is the easy synthetic method of the expanded porphyrins that are macrocycles comprising of alternate arrangement of more than six of pyrrole units bridged by a methine group whose hydrogen is substituted with Ar-group. These expanded porphyrins are obtained by reacting pyrrole with 2,6 substituted benzaldehydes which can possess a substituent at other position, 9-formylanthracene which can possess substituent, or cyclohexane carboardehydes which can possess substituent under the presence of acid catalyst at the substrate concentration of larger than 6xc3x9710xe2x88x922 mol/L followed by oxidation with a suitable oxidant, (wherein Ar is either 2,6-substituted phenyl group which can possess a substituent on the other 3, 4, and 5 position, or a 9-anthryl group which can possess a substituent, or a cyclohexyl group which can possess a substituent. The said substituent at 2 and 6 positions can be selected independently from the group consisting of fluoro, chloro, bromo, iodide, lower alkyl of carbon number 1 to 4 or lower alkoxy, substituent at 3-5 positions, 9-anthranil group and cyclohexyl group can be selected independently from the group consisting of substituted or non-substituted alkyl of carbon number 5 or 6, alkenyl group, alkynyl group, substituted or non-substituted aryl group, alkyl or aryl sulfonyl group, alkyl or aryl cyano group, cyano group, nitro group, amino group, carboxy group, carboalkoxy group or ester, amide and salt thereof and specific group having well-known target specific besides above mentioned substituents at 2 and 6 positions. Each Ar can be different).